Although the brain has a high metabolic demand, it has a low capacity for storing energy and is dependent on a continuous supply of glucose from the circulation. Disturbed brain metabolism is a well- characterized secondary pathology of Traumatic Brain Injury (TBI). A biphasic change in brain glucose metabolism has been documented in which an acute, transient increase in brain glucose metabolism is followed by a prolonged suppression in metabolism lasting for days. This decreased glucose metabolism occurs in the absence of ischemia and in brain regions critical to cognition such as the hippocampus and the neocortex. There are four primary classes of mammalian glucose transporters, Glut 1-4, with Glut3 being the principal glucose transporter for neurons. However, a recent study has demonstrated that Glut3 expression patterns did not correlate with brain glucose uptake in a linear manner, a disparity that was especially evident in the hippocampus. Glut4 is expressed at high levels in muscle and adipose tissue, and is unique in that under basal conditions, a relatively large proportion of the transporter is retained in intracellular Glut4- containing storage vesicles (GSVs). Recent studies have shown that the energy sensor AMP-activated protein kinase (AMPK) can mobilize Glut4 by phosphorylating the regulatory molecule AS160. As TBI alters brain glucose metabolism, it is plausible that this will result in a change in AMPK activity and Glut4 mobilization within the injured brain. While the role of Glut4 in energy metabolism in the periphery is well appreciated, its role in TBI pathophysiology has not been examined. We propose to test the hypotheses that Glut4 acts to protect neurons and lessen TBI-associated memory impairments. Its mobilization by activators of AMPK will offer neuroprotection and improve memory in brain injured animals. We outline three Specific Aims to test the above hypotheses. Specific Aim 1: Determine if manipulating Glu4 activity/levels can influence neuroprotection. Specific Aim 2: Determine if increasing Glut4 mobilization offers neuroprotection. Specific Aim 3: Examine if activators of AMPK can improve memory in TBI animals. These experiments will examine if modulating Glut4 expression can be used a potential therapeutic and will reveal the influence of this transporter on the neuronal death and dysfunction associated with TBI. The proposed studies have translational relevance and, if successful, may have implications for other neurological disorders and diseases in which altered brain metabolism are features.